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Home » Magnified insets (white frames) show detail of primary cilia (arrowheads) in the embryo; 4V, fourth ventricle

Magnified insets (white frames) show detail of primary cilia (arrowheads) in the embryo; 4V, fourth ventricle

Magnified insets (white frames) show detail of primary cilia (arrowheads) in the embryo; 4V, fourth ventricle. pathognomonic for JBTS (including cerebellar hypoplasia), and retention of abnormal bulbous cilia associated with mild neural tube ventralization. The JBTS-like group TAS4464 had de-regulated low levels of canonical Wnt signalling associated with the loss of Dvl-1 localization to the basal body. Our results suggest that modifier alleles partially determine the variation between MKS and JBTS, implicating the interaction between Dvl-1 and meckelin, or other components of the ciliary transition zone. The line is unique in modelling the variable expressivity of phenotypes in these two ciliopathies. INTRODUCTION MeckelCGruber syndrome (MKS) is a lethal ciliopathy disorder that is usually diagnosed upon detection of a triad of manifestations that include renal cystic kidney dysplasia, polydactyly and neurodevelopment anomalies (1,2). The central nervous system (CNS) defects commonly observed in MKS include occipital encephalocele, rhombic roof dysgenesis and prosencephalon dysgenesis. The latter may include olfactory bulb dysgenesis, optic nerve hypoplasia, agenesis of the corpus callosum or total holoprosencephaly. These defects are thought to be caused by an underlying defect in ventral induction of the developing CNS by the prochordal mesoderm (3). Other occasional CNS features of MKS include microcephaly, cerebellar hypoplasia or total anencephaly (4). The human condition is usually both genetically and phenotypically heterogenous, and displays marked phenotypic and genetic overlap with the allelic neurodevelopmental disorder Joubert syndrome (JBTS) (5). JBTS neurodevelopmental phenotypes involve cerebellar vermis hypoplasia or aplasia, a deep interpeduncular fossa and narrowing of the midbrain tegmentum. Collectively, these features are visualized on axial MRI with the characteristic molar tooth sign (MTS) that is pathognomonic for this condition (6). MKS and JBTS are ciliopathies (5,7C9), caused by mutations in genes encoding proteins that are components of the primary cilium and basal body. Primary cilia are microtubule-based organelles that sense and transduce extracellular signals on many cell types during the TAS4464 G1/G0 phase of the cell cycle (10C12), and it is now well established that cilia mediate key pathways of embryonic development such as Wnt and Shh signalling (13,14). The role of cilia in regulating canonical (-catenin-mediated) Wnt remains unclear, with some studies showing that cilia act as a negative regulator of canonical Wnt signalling, suggesting that the loss of cilia leads to activation of the canonical Wnt signalling. For example, high levels of cytoplasmic and nuclear -catenin were present in postnatal cystic kidneys (15) and pancreas (16) of animal models with mutations in and IFT genes, respectively. These findings suggest that -catenin degradation is usually a process that requires cilia and/or basal bodies. In addition, members of the destruction complex, Gsk-3 (17) and APC (18), are localized to cilia, and primary cilia restrict the activity of canonical Wnt signalling pathway in mouse embryo, primary fibroblast and embryonic stem cells. Recently, Lancaster (19) confirmed that primary cilia constrain canonical Wnt signalling through -catenin cytosolic stabilization, whereas cells with multiple cilia have suppressed canonical Wnt/-catenin signalling. In contrast, studies in other Rabbit Polyclonal to U51 ciliopathy models with cilia defects demonstrate that this Wnt pathway was not disrupted in zebrafish (20) or mouse embryos (21). This may suggest a context-dependant regulation of canonical Wnt signalling by primary cilia. To further TAS4464 elucidate the role of Shh and Wnt signalling in the severe human ciliopathies such as MKS with occipital encephalocele TAS4464 and JBTS, and the possible molecular basis for the variability of the neurodevelopmental anomalies, we studied embryonic neurodevelopmental, cilia and Wnt/-catenin signalling phenotypes in the knockout mouse line (22). encodes Tmem67 (transmembrane protein 67 or meckelin), a 995 amino-acid transmembrane protein (Supplementary Material, Fig. S1A), with structural similarity to Frizzled receptors (23). TAS4464 Meckelin/TMEM67 contains an extracellular N-terminal domain name with a highly conserved cysteine-rich repeat domain name (CRD), a predicted -pleated sheet region and seven predicted transmembrane regions (Supplementary Material, Fig..


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